Engineering Yeast Transcription Machinery for Improved Ethanol Tolerance and Production
Abstract
Global transcription machinery engineering (gTME) is an approach for reprogramming gene transcription to elicit cellular phenotypes important for technological applications. Here we show the application of gTME to Saccharomyces cerevisiae for improved glucose/ethanol tolerance, a key trait for many biofuels programs. Mutagenesis of the transcription factor Spt15p and selection led to dominant mutations that conferred increased tolerance and more efficient glucose conversion to ethanol. The desired phenotype results from the combined effect of three separate mutations in the SPT15 gene [serine substituted for phenylalanine (Phe 177 Ser) and, similarly, Tyr 195 His, and Lys 218 Arg]. Thus, gTME can provide a route to complex phenotypes that are not readily accessible by traditional methods.
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Laboratory selection can lead to large-scale rewiring of gene regulatory networks, but an approach called gTME, global transcription machinery engineering, can also yield similar results.
“For example, laboratory selection can lead to large-scale rewiring of gene regulatory networks, but an approach, that the authors called gTME, global transcription machinery engineering, can also yield similar results [2].”
From Adaptive laboratory evolution—Principles and applications for biotechnology (2013) · cites this paper as [2]
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“In an interesting study by Alper et al. (2006), engineering of a transcription factor allowed global perturbations of the transcriptome for improved ethanol tolerance and production in the budding yeast Saccharomyces cerevisiae.”
BackgroundBaez, A., Cho, K.-M., & Liao, J. C. (2011) · Applied Microbiology and Biotechnology · doi:10.1007/s00253-011-3173-y · Cited by 255 · see citing works
“In this sense, improving the tolerance of the biocatalyst becomes a primary necessity to achieve a process with high product titers (Alper et al. 2006; Gonzalez et al. 2003; Jarboe et al. 2010; Miller and Ingram 2007; Yomano et al. 1998).”
BackgroundAdegboye, M. F., Ojuederie, O. B., Talia, P. M., & Babalola, O. O. (2021) · Biotechnology for Biofuels · doi:10.1186/s13068-020-01853-2 · Cited by 259 · see citing works
Mechanisms of yeast stress tolerance and its manipulation for efficient fuel ethanol production
Zhao, X., & Bai, F. (2009) · Journal of Biotechnology · doi:10.1016/j.jbiotec.2009.05.001 · Cited by 244 · see citing works
Genome-wide identification of Saccharomyces cerevisiae genes required for tolerance to acetic acid
Mira, N. P., Palma, M., Guerreiro, J. F., & Sá‐Correia, I. (2010) · Microbial Cell Factories · doi:10.1186/1475-2859-9-79 · Cited by 241 · see citing works
“The manipulation of yeast transcriptional machinery to increase the expression of genes conferring resistance to ethanol and high glucose concentrations was found to be a successful approach to improve the performance of yeast alcoholic fermentations [56].”
BackgroundRETRACTED: Lignocellulosic ethanol in India: Prospects, challenges and feedstock availability
Sukumaran, R. K., Surender, V. J., Sindhu, R., Binod, P., Janu, K. U., Sajna, K. V., Rajasree, K. P., & Pandey, A. (2009) · Bioresource Technology · doi:10.1016/j.biortech.2009.11.049 · Cited by 241 · see citing works
RetractedSynthetic Biology: An Emerging Engineering Discipline
Cheng, A. A., & Lu, T. K. (2012) · Annual Review of Biomedical Engineering · doi:10.1146/annurev-bioeng-071811-150118 · Cited by 241 · see citing works
“Genetic engineering has enabled corresponding improvements in biofuel tolerance (95), the expansion of the range of carbon source inputs (96), and enhanced yields (97).”
BackgroundMicrobial production of building block chemicals and polymers
Lee, J. W., Kim, H. U., Choi, S., Yi, J., & Lee, S. Y. (2011) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2011.02.011 · Cited by 232 · see citing works
Engineering tolerance to industrially relevant stress factors in yeast cell factories
Deparis, Q., Claes, A., Foulquié-Moreno, M. R., & Thevelein, J. M. (2017) · FEMS Yeast Research · doi:10.1093/femsyr/fox036 · Cited by 231 · see citing works
“This was first accomplished by Alper and co-workers (Alper et al. 2006; Ding et al. 2009), who created a strain with increased ethanol tolerance caused by an altered TATA-binding protein Spt15.”
BackgroundEngineering bacteria for production of rhamnolipid as an agent for enhanced oil recovery
Wang, Q., Fang, X., Bai, B., Liang, X., Shuler, P. J., Goddard, W. A., & Tang, Y. (2007) · Biotechnology and Bioengineering · doi:10.1002/bit.21462 · Cited by 229 · see citing works
“The mutagenesis of transcription machinery or some other genes would change the global transcription regulation and elicit cellular phenotypes important for technological application (Alper et al., 2006).”
BackgroundInnovation and strategic orientations for the development of advanced biorefineries
Dragone, G., Kerssemakers, A. A. J., Driessen, J. L. S. P., Yamakawa, C. K., Brumano, L. P., & Mussatto, S. I. (2020) · Bioresource Technology · doi:10.1016/j.biortech.2020.122847 · Cited by 226 · see citing works
Chen, X., Zhou, L., Tian, K., Kumar, A., Singh, S., Prior, B. A., & Wang, Z. (2013) · Biotechnology Advances · doi:10.1016/j.biotechadv.2013.02.009 · Cited by 224 · see citing works
“coli and yeasts (Alper et al., 2006; Portnoy et al., 2011).”
Expanding the metabolic engineering toolbox: more options to engineer cells
Tyo, K. E. J., Alper, H. S., & Stephanopoulos, G. N. (2007) · Trends in biotechnology · doi:10.1016/j.tibtech.2007.01.003 · Cited by 215 · see citing works
“In doing so, several proof-of-concept studies have been obtained, including increasing cellular tolerances (including increased ethanol tolerance) [ 51 ], metabolic overproduction (including lycopene production) and multiple phenotypes (including multiple tolerance phenotypes) [52].”
BackgroundSelf-citationEngineering alcohol tolerance in yeast
Lam, F. H., Ghaderi, A., Fink, G. R., & Stephanopoulos, G. N. (2014) · Science · doi:10.1126/science.1257859 · Cited by 213 · see citing works
Self-citationHow microbes tolerate ethanol and butanol
Liu, S., & Qureshi, N. (2009) · New Biotechnology · doi:10.1016/j.nbt.2009.06.984 · Cited by 208 · see citing works
Metabolic Engineering: Methodologies and Applications
Volk, M., Tran, V. G., Tan, S., Mishra, S., Fatma, Z., Boob, A. G., Li, H., Xue, P., Martin, T. A., & Zhao, H. (2022) · Chemical Reviews · doi:10.1021/acs.chemrev.2c00403 · Cited by 204 · see citing works
Separation, hydrolysis and fermentation of pyrolytic sugars to produce ethanol and lipids
Lian, J., Chen, S., Zhou, S., Wang, Z., O’Fallon, J. V., Li, C., & Garcı̀a-Pèrez, M. (2010) · Bioresource Technology · doi:10.1016/j.biortech.2010.07.071 · Cited by 209 · see citing works
“S. cerevisiae was selected for ethanol production because of its high ethanol yield, high productivity, and high ethanol tolerance (Alper et al., 2006).”
BackgroundTeixeira, M. C., Raposo, L. R., Mira, N. P., Lourenço, A. B., & Sá‐Correia, I. (2009) · Applied and Environmental Microbiology · doi:10.1128/aem.00845-09 · Cited by 208 · see citing works
“Throughout the years many efforts to characterize the mechanisms underlying ethanol stress tolerance, aiming to increase ethanol productivity, have been made (3, 16, 45, 53).”
BackgroundDietrich, J. A., Shis, D. L., Alikhani, A., & Keasling, J. D. (2012) · ACS Synthetic Biology · doi:10.1021/sb300091d · Cited by 206 · see citing works
Chandel, A. K., & Singh, O. V. (2010) · Applied Microbiology and Biotechnology · doi:10.1007/s00253-010-3057-6 · Cited by 202 · see citing works
“Alper et al. (2006) called this cellular engineering approach “global transcription machinery engineering”; it includes the alteration of key proteins regulating the global transcriptome and generates, through them, a new type of diversity at the transcriptional level.”
BackgroundStrain engineering for improved expression of recombinant proteins in bacteria
Makino, T., Σκρέτας, Γ., & Georgiou, G. (2011) · Microbial Cell Factories · doi:10.1186/1475-2859-10-32 · Cited by 200 · see citing works
“Screening of plasmid-encoded gTME libraries was used to isolate strains with increased tolerance to alcohols and for enhanced production of small molecules, such as lycopene (50% increase), L-tyrosine (150% increase), hyaluronic acid (60% increase), and others [55,66-68].”
BackgroundBiotechnology of non-Saccharomyces yeasts—the ascomycetes
Johnson, E. A. (2013) · Applied Microbiology and Biotechnology · doi:10.1007/s00253-012-4497-y · Cited by 193 · see citing works
“Metabolic engineering and modeling of the biochemical pathways involved in the fermentation of pentoses and other carbon sources are being exploited to enhance fermentation productivity, as well as other limiting factors such as ethanol resistance (Alper et al. 2006; Flores et al. 2000; Ostergaard et al. 2000; Stephan…”
BackgroundSystems metabolic engineering for chemicals and materials
Lee, J. W., Kim, T. Y., Jang, Y., Choi, S., & Lee, S. Y. (2011) · Trends in biotechnology · doi:10.1016/j.tibtech.2011.04.001 · Cited by 194 · see citing works
Microbial production of advanced transportation fuels in non-natural hosts
Connor, M. R., & Liao, J. C. (2009) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2009.04.002 · Cited by 193 · see citing works
Chen, X., Gao, C., Guo, L., Hu, G., Luo, Q., Liu, J., Nielsen, J., Chen, J., & Liu, L. (2017) · Chemical Reviews · doi:10.1021/acs.chemrev.6b00804 · Cited by 193 · see citing works
Mutant alcohol dehydrogenase leads to improved ethanol tolerance in Clostridium thermocellum
Brown, S. D., Guss, A. M., Karpinets, T. V., Parks, J. M., Smolin, N., Yang, S., Land, M., Klingeman, D. M., Bhandiwad, A., Rodríguez, M., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1102444108 · Cited by 191 · see citing works
“many genes simultaneously through a single genetic modification (16).”
BackgroundBorden, J. R., & Papoutsakis, E. T. (2007) · Applied and Environmental Microbiology · doi:10.1128/aem.02296-06 · Cited by 190 · see citing works
“Transcriptional regulators are important for tolerant phenotypes (1, 5, 30).”
BackgroundDevelopment of biosensors and their application in metabolic engineering
Zhang, J., Jensen, M. K., & Keasling, J. D. (2015) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2015.05.013 · Cited by 186 · see citing works
“On the other hand, non-targeted methods, such as directed evolution, have also proven effective in generating cell factories with improved performance (Figure 1) [3–7].”
MethodFan, L., Zhang, Z., Yu, X., Xue, Y.-X., & Tan, T. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1209856109 · Cited by 185 · see citing works
“Saccharomyces cerevisiae is an ideal engineered candidate for CBP to achieve the simultaneous cellulose saccharification and ethanol fermentation, because it has high ethanol productivity, strong ethanol tolerance, and clear hereditary information (7, 8).”
BackgroundProgramming adaptive control to evolve increased metabolite production
Chou, H. H., & Keasling, J. D. (2013) · Nature Communications · doi:10.1038/ncomms3595 · Cited by 184 · see citing works
“The rrf genes encode the 50S subunit of the ribosome, and mutations in these genes are in accordance with the previous efforts to modify the E. coli and S. cerevisiae transcription machineries 31,32 .”
ResultFeasibilities of consolidated bioprocessing microbes: From pretreatment to biofuel production
Parisutham, V., Kim, T. H., & Lee, S. K. (2014) · Bioresource Technology · doi:10.1016/j.biortech.2014.03.114 · Cited by 184 · see citing works
Biosensor-driven adaptive laboratory evolution of l-valine production in Corynebacterium glutamicum
Mahr, R., Gätgens, C., Gätgens, J., Polen, T., Kalinowski, J., & Frunzke, J. (2015) · Metabolic Engineering · doi:10.1016/j.ymben.2015.09.017 · Cited by 178 · see citing works
“Furthermore, engineering of S. cerevisiae for increased ethanol tolerance was associated with the improvement in ethanol production from glucose (Alper et al., 2006).”
Towards systems metabolic engineering of microorganisms for amino acid production
Park, J. H., & Lee, S. Y. (2008) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2008.08.007 · Cited by 171 · see citing works
Combinatorial engineering of microbes for optimizing cellular phenotype
Santos, C. N. S., & Stephanopoulos, G. N. (2008) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2008.01.017 · Cited by 172 · see citing works
Self-citationEnergy optimization for the design of corn‐based ethanol plants
Karuppiah, R., Peschel, A., Grossmann, I. E., Martı́n, M., Martinson, W., & Zullo, L. (2008) · AIChE Journal · doi:10.1002/aic.11480 · Cited by 167 · see citing works
“Model (P1) comprises constraints (1)–(178), where the binary parameter is set to 1 and is set to 0.”
BackgroundInfluentialBiotechnological advances in UDP-sugar based glycosylation of small molecules
Bruyn, F. D., Maertens, J., Beauprez, J. J., Soetaert, W., & Mey, M. D. (2015) · Biotechnology Advances · doi:10.1016/j.biotechadv.2015.02.005 · Cited by 167 · see citing works
Synthetic RNA devices to expedite the evolution of metabolite-producing microbes
Yang, J., Seo, S. W., Jang, S., Shin, S.-I., Lim, C. H., Roh, T., & Jung, G. Y. (2013) · Nature Communications · doi:10.1038/ncomms2404 · Cited by 166 · see citing works
Abbott, D. A., Zelle, R. M., Pronk, J. T., & van Maris, A. J. A. (2009) · FEMS Yeast Research · doi:10.1111/j.1567-1364.2009.00537.x · Cited by 164 · see citing works
“cerevisiae (Alper et al., 2006) and E.”
BackgroundEngineering of an Escherichia coli Strain for the Production of 3-Methyl-1-Butanol
Connor, M. R., & Liao, J. C. (2008) · Applied and Environmental Microbiology · doi:10.1128/aem.00468-08 · Cited by 163 · see citing works
“Also, a variety of methods have been developed to increase tolerance to alcohol stress in various organisms (2, 6, 24), which may be applied to E.”
BackgroundOptimizing pentose utilization in yeast: the need for novel tools and approaches
Young, E. M., Lee, S., & Alper, H. S. (2010) · Biotechnology for Biofuels · doi:10.1186/1754-6834-3-24 · Cited by 158 · see citing works
“Importantly, improving cellular tolerances is possible, although underused [103].”
BackgroundInfluentialSelf-citationExploring the potential of genome editing CRISPR-Cas9 technology
Singh, V., Braddick, D., & Dhar, P. K. (2016) · Gene · doi:10.1016/j.gene.2016.11.008 · Cited by 164 · see citing works
“Similarly, synthetic small RNAs have been used for improving tyrosine and cadaverine production (Na et al., 2013), and global transcription machine engineering (gTME) has been used to improve ethanol tolerance (Alper et al., 2006).”
MethodHaft, R. J. F., Keating, D. H., Schwaegler, T., Schwalbach, M. S., Vinokur, J. M., Tremaine, M. T., Peters, J. M., Kotlajich, M. V., Pohlmann, E. L., Ong, I. M., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1401853111 · Cited by 157 · see citing works
“For example, increased alcohol tolerance of strains with reduced Rho activity (14, 20) or mutations in RNA polymerase subunits or the TATAbinding protein (4, 22, 63) have been attributed to altered expression of specific genes controlled by termination or initiation.”
Background
- Authors
- Alper, H., Moxley, J., Nevoigt, E., Fink, G. R., & Stephanopoulos, G.
- Affiliations
- Whitehead Institute for Biomedical Research (US)
- Corresponding author
- Stephanopoulos, Gregory
- Venue
- Science
- Published
- 2006-12-08
- Volume
- 314
- Issue
- 5805
- Pages
- 1565-1568
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2080537888
- Cited by
- 823
- References
- 26
- Citations by year
- 2026: 10 · 2025: 23 · 2024: 31 · 2023: 18 · 2022: 28 · 2021: 39 · 2020: 43 · 2019: 37 · 2018: 39 · 2017: 44 · 2016: 49 · 2015: 61 · 2014: 55 · 2013: 57 · 2012: 68
- FWCI
- 14.67
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (GM035010)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Microbial Metabolic Engineering and Bioproduction
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Physical Sciences › Engineering › Biomedical Engineering › Biofuel production and bioconversion
- Keywords
- Saccharomyces cerevisiae, ethanol tolerance, glucose fermentation, transcription factor mutations, dominant mutations, biofuel production, yeast strain engineering
- MeSH terms
- Ethanol, Fermentation, Genetic Engineering, Glucose, Phenotype, Saccharomyces cerevisiae, Transcription Factors, Transcription, Genetic, Transformation, Genetic, Up-Regulation, Gene Expression Regulation, Fungal, Mutagenesis, Cell Cycle Proteins, Amino Acid Substitution, Gene Expression Profiling, Saccharomyces cerevisiae Proteins, TATA-Box Binding Protein, Transcription Factor TFIID, TATA-Binding Protein Associated Factors
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